Submissions for variant NM_000277.3(PAH):c.916A>G (p.Ile306Val)

gnomAD frequency: 0.00003  dbSNP: rs62642934

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000169485	SCV000852135	pathogenic	Phenylketonuria	2018-08-10	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PM2: MAF = 2.0e-5; PP3: Software agrees on a damaging effect.; PS3: Mutation ID#1, 18% residual enzyme activity (PMID:18590700); PM3: I306V / F55L (pathogenic in ClinVar) in a single patient with mild HPA (PMID:18299955); PP4_Moderate: BH4 defect excluded in all patients--single patient with mild hyperphe (Bercovich, 2008). (PMID:18299955). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PM3, PP4_Moderate).
Fulgent Genetics, Fulgent Genetics	RCV000169485	SCV000611226	likely pathogenic	Phenylketonuria	2017-05-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169485	SCV000696473	pathogenic	Phenylketonuria	2017-05-22	criteria provided, single submitter	clinical testing	Variant summary: The PAH c.916A>G (p.Ile306Val) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/121200 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). The variant was reported in numerous individuals in the literature, mainly associated with mild-PKU or hyperphenylalaninemia. In addition, in vitro assays show the variant to result in reduced PAH activity. Multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169485	SCV000833414	pathogenic	Phenylketonuria	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 306 of the PAH protein (p.Ile306Val). This variant is present in population databases (rs62642934, gnomAD 0.003%). This missense change has been observed in individuals with PAH-related disease (PMID: 1358789, 18299955, 23430547, 23764561). ClinVar contains an entry for this variant (Variation ID: 618). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PAH protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 11161839, 17924342, 25596310). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000089157	SCV001249174	pathogenic	not provided	2019-06-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169485	SCV004209608	pathogenic	Phenylketonuria	2023-12-26	criteria provided, single submitter	clinical testing
OMIM	RCV000000649	SCV000020799	pathogenic	Hyperphenylalaninemia	1992-09-01	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089157	SCV000119771	not provided	not provided		no assertion provided	not provided
Counsyl	RCV000169485	SCV000220937	pathogenic	Phenylketonuria	2016-01-21	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000169485	SCV001463131	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing